Zinc-Mediated Radical-Type Cross-Electrophile Couplings of Trifluoromethyl Alkenes with Alkyl Iodides for Accessing -Difluoroalkenes in Aqueous Media.

The cross-electrophile couplings of trifluoromethyl alkenes with alkyl iodides could be successfully realized in aqueous media in the presence of Zn powder, CuI, and TBAI. The defluorinative reactions proceeded effectively at ambient temperature under transition metal catalyst-free conditions via C-F bond cleavage to afford a broad range of synthetically useful -difluoroalkenes in moderate to excellent yields. Both wide substrate generality (broadly applicable to primary, secondary, and tertiary alkyl iodides) and excellent functional group compatibility could be achieved.

Palladium-Catalyzed α-Arylation of Nitroalkanes with Aryl Fluorosulfonates for Convenient Access to α-Arylated Nitroalkanes.

Palladium-catalyzed α-arylation of nitroalkanes by utilizing aryl fluorosulfonates as effective arylating agents can be realized. The reactions proceed effectively through C-O bond activation to produce a variety of valuable α-arylated nitroalkanes in modest to good yields with wide functional group compatibility. Additionally, late-stage functionalization of complex molecules and scale-up synthesis can be achieved.

C-P to C-P(O) Bond Exchange of Organophosphonium Salts: Synthesis of 3-(Phosphoryl)methylindoles under Additive- and Catalyst-Free Conditions.

A straightforward, mild, additive-free, and catalyst-free method for the phosphorylation of indolyl-containing quaternary phosphonium salts with phosphine oxides has been developed. This process involves a formal C-P to C-P(O) bond exchange, encompassing the cleavage of a C-P bond and the formation of a C-P(O) bond. Through this method, a variety of structurally diverse and potentially bioactive 3-(phosphoryl)methylindoles were synthesized in moderate to good yields with good functional group tolerance.

Palladium-Catalyzed Decarboxylative Cross-Couplings of Zinc Polyfluorobenzoates with Aryl 2-Pyridyl Esters for Accessing Polyfluorinated Aryl Ketones.

An efficient decarboxylative cross-coupling of zinc polyfluorobenzoate with aryl 2-pyridyl ester under palladium catalysis, which enabled the convenient access to valuable polyfluorinated aryl ketones, was developed. The cross-coupling reactions proceeded effectively to give an array of polyfluorinated aryl ketones in moderate to excellent yields with a reasonable substrate scope and broad functional group tolerance. In addition, a one-pot reaction with the use of in situ formed zinc polyfluorobenzoate commencing from polyfluorobenzoic acid and Zn(OH) could be accomplished as well in a step-economical fashion.

Pd-catalyzed decarboxylative coupling of zinc polyfluorobenzoate with aryl imidazolylsulfonate for polyfluorinated biaryl synthesis.

We report here an efficient decarboxylative cross-coupling of zinc polyfluorobenzoates with aryl imidazolylsulfonates under palladium catalysis, which proceeded effectively C-O bond cleavage to afford the corresponding valuable polyfluorinated biaryls in moderate to good yields, exhibiting both reasonable substrate scope and broad functional group tolerance. In addition, late-stage functionalization of bioactive molecules and an amino acid-derived compound and scaled-up synthesis could be accomplished as well. Further exploration revealed that zinc polyfluorobenzoates are more vibrant than their potassium, sodium, and magnesium counterparts as a polyfluoroarylating reagent.

Iron-Mediated One-Pot Dehydroxylative Cross-Electrophile Coupling of Alcohol with Disulfide for Thioether Synthesis by Using TCT as a Hydroxyl-Activating Agent.

An efficient dehydroxythiolation between alcohols and disulfides using the widely abundant and cheapest iron as a reaction mediator was developed. The one-pot thiolation proceeded effectively via C-O bond activation with the aid of cyanuric chloride (TCT) as a hydroxyl-activating agent to give the corresponding thioethers in modest to excellent yields, displaying both a wide substrate scope (applicable to benzyl alcohol, allyl alcohol, and primary alkyl alcohol) and good functional group tolerance. In addition, diselenide was also proven to be an appropriate substrate for the protocol, and the reaction could be subjected to scale-up synthesis.

Synthesis of Polyfluorinated Biaryls via Palladium-Catalyzed Decarboxylative Cross-Coupling of Zinc Polyfluorobenzoates with Aryl Fluorosulfates.

A palladium-catalyzed decarboxylative cross-coupling of zinc polyfluorobenzoates with aryl fluorosulfates, which proceeded efficiently via C-O bond cleavage to afford the corresponding polyfluorinated biaryls in moderate-to-good yields, was developed. The reactions exhibited both good substrate scope and broad functional group compatibility, and it could be scaled-up easily. The synthetic simplicity and practicability of the reaction was further demonstrated by one-pot manipulation by directly mixing polyfluorobenzoic acid and Zn(OH) in the coexistence of aryl fluorosulfate and a palladium catalyst in one flask.

Water-Involved 1,3-Aminoxylation of Fluoroalkenes: Chemo-, Regio-, and Stereoselective Synthesis of β-Fluoroacyl Vinylamines.

Perfluoroalkyl alkenyl iodides (PFAIs) are emerging as highly reactive, storage-stable, and multifunctional fluoroalkyl-bearing reagents, facilitating the manufacture of value-added organofluorides through multi-halo-functionalization. Herein, we developed a water-involved 1,3-aminoxylation of PFAIs with sulfonamides for the chemo-, regio-, and -stereoselective synthesis of valuable β-fluoroacyl vinylamines. This reaction proceeded via a sequential deiodoamination and defluoroxylation process under transition-metal-free conditions, featuring a broad substrate scope and good functional group tolerance.

[4+2] Defluorocycloaddition of Perfluoroalkyl Alkynes and Benzylamines: Synthesis of -Fluoroalkylated Pyridin-4-amines.

Pyridines represent privileged heterocycles, and the ability to produce fluorinated pyridines from polyfluorinated substances through selective defluorofunctionalization is a new addition to their synthesis. Herein, an unprecedented formal [4+2] defluorocycloaddition of perfluoroalkyl alkynes and benzylamines under metal-free conditions is described. By leveraging the functionalization of four C(sp)-F bonds on two vicinal sterically hindered perfluoroalkyl carbons of perfluoroalkyl alkynes, a diverse array of -fluoroalkylated pyridin-4-amines were synthesized with good functional group tolerance.

Perfluoroalkyl Editing of Fluoroalkynes: Chemo-, Regio-, and Stereoselective Synthesis of ()-(2-Amino-fluoroalkenyl)pyrimidines.

A chemo-, regio-, and stereoselective condensation reaction of perfluoroalkyl alkynes (PFAAs), (CHO), and (NH)CO through the cleavage of five inert C(sp)-F bonds at three distinct carbon sites, thereby establishing an unprecedented platform for synthesizing structurally unique ()-(2-amino-fluoroalkenyl)pyrimidines, is first developed. Remarkably, this reaction features mild reaction conditions, good compatibility with various functional groups, excellent -stereoselectivity, late-stage modification of complex molecules, scalability, and versatile synthetic transformations of the resulting heterocyclic compounds.

Three-Component Sulfonylation and Heteroannulation Enabled by 3-Fold Defluorofunctionalization of Trifluoromethyl Enones.

Trifluoromethyl enone emerges as a versatile and multifaceted building block in organic synthesis. A defluorinative heterocyclization reaction of readily available β,β-ditrifluoromethylated enones and biocompatible sodium sulfinates has been developed for the modular synthesis of densely functionalized furans with regio-defined 2,4-bissulfonyl and 3-trifluoromethyl substitutions. This three-component method proceeds through a sequential sulfonylation and intramolecular -cyclization, enabling the assembly of one furan ring, the formation of C-SO/C-O bonds, and the cleavage of three C(sp)-F bonds in a one-pot manner under transition metal-free conditions.

Sulfinate-Promoted Defluorinative Cyclization of Polyfluoroalkyl Tetralones Enabled by Photocatalysis.

A Ru-catalyzed defluorinative cyclization of polyfluoroalkyl tetralones has been developed under visible-light irradiation for the precise assembly of γ-pyrones featuring α-perfluoroalkyl and β-fluorine substituents. Selective functionalization of five C(sp)-F bonds at three carbon sites on the perfluoroalkyl chain provides a new mode for utilizing polyfluorides as versatile synthons to access difficult-to-obtain heterocyclic scaffolds. Moreover, the sulfinate salt serves dual roles as an oxygen source for creating the carbonyl group and as a defluorinating promoter.

Direct Cross-Couplings of Aryl Nonaflates with Aryl Bromides under Nickel Catalysis.

The direct cross-couplings of aryl nonaflates with aryl bromides could be successfully accomplished by utilizing nickel as the catalyst, magnesium as the metal mediator, and lithium chloride as the additive. The reactions proceeded efficiently in THF at room temperature to produce the desired biaryls in moderate to good yields, showing both a reasonable substrate scope and functional group tolerance. Additionally, an equally good performance could be realized when the reaction was subjected to scale-up synthesis.

Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp)─F Bonds Functionalization.

Introducing distinctive functional groups to expand the structural diversity and improve the intrinsic properties of parent molecules has been an essential pursuit in organic chemistry. By using perfluoroalkyl halide (PFAH) as a nontraditional, readily available, ideal 1,2-difluoroalkenyl coupling partner, a defluorinative cyclization reaction of enamides for the construction of fluoroalkenyl oxazoles is first developed. The selective and controllable two-fold cleavage of vicinal C(sp)─F bonds in PFAH not only enables the introduction of a specific 1,2-difluoroalkenyl moiety with ease but also results in the functionalization of two C(sp)─H bonds of enamides without the need for metal catalyst, photocatalyst, oxidant, or light.

Modular Synthesis of Furans with Four Nonidentical Substituents by Aqueous Defluorinative Reaction of Trifluoromethyl Enones with Two Nucleophiles.

A three-component reaction of trifluoromethyl enones, phosphine oxides, and alcohols in water solution is developed. This defluorinative reaction occurs through a cascade process involving defluorophosphorylation, defluoroalkyloxylation, and defluoroheteroannulation, enabling the modular synthesis of furans with four distinct substituents: 2-alkyloxy, 3-trifluoromethyl, 4-phosphoryl, and 5-(hetero)aryl groups. Moreover, apart from alcohol substrates, the scope of nucleophiles could be further extended to phenols, azacycles, or sulfonamide.

Defluorinative Diazolation-Cyclization Relay for Synthesis of Furan-Bridged Triheterocycles and Colorimetric Sensor Application.

Polyaromatics, as the assembly of diverse cyclic π-systems, exhibit unique physicochemical properties when compared to their individual constituents. In this study, we developed a strategic connection of two azacycles via a furan bridge through a defluorinative diazolation-cyclization reaction of trifluoromethyl enones and N-heterocycles. A range of modular 2,4-furan-bridged triheterocycles (FBTHs), featuring a C3-trifluoromethyl group, was synthesized with broad substrate scope and good regioselectivity under transition metal-free conditions.

Palladium-Catalyzed Cross-Electrophile Couplings of Aryl Thianthrenium Salts with Aryl Bromides via C-S Bond Activation.

We report here a step-economic and cost-effective cross-electrophile coupling of aryl thianthrenium salts with widely available aryl bromides, which proceeded effectively via C-S bond activation at ambient temperature in THF in the presence of a palladium catalyst, magnesium turnings, and lithium chloride to enable the facile assembly of a wide array of structurally diverse biaryls in modest to good yields with good functional group compatibility. In addition, the gram-scale reaction could also be realized.

Magnesium-Mediated Cross-Electrophile Couplings of Aryl 2-Pyridyl Esters with Aryl Bromides for Ketone Synthesis through In Situ-Formed Arylmagnesium Intermediates.

Aryl 2-pyridyl esters could efficiently undergo cross-electrophile couplings with aryl bromides with the aid of magnesium as a reducing metal in the absence of a transition-metal catalyst, leading to the unsymmetrical diaryl ketones in modest to good yields with wide functionality compatibility. In addition, the reaction could be easily scaled up and applied in the late-stage modification of biologically active molecules. Preliminary mechanistic study showed that the coupling reaction presumably proceeds through the in situ formation of arylmagnesium reagents as key intermediates.

Cross-Electrophile Couplings of Benzyl Sulfonium Salts with Thiosulfonates via C-S Bond Activation.

A zinc-mediated cross-electrophile coupling of benzyl sulfonium salts with thiosulfonates via C-S bond cleavage was achieved. The reductive thiolation proceeded well under transition metal-free conditions to afford the desired benzyl sulfides in good yields, exhibiting both broad substrate scope and good functionality tolerance. In addition, the reaction could be applied to the use of selenosulfonate as an effective selenylation agent and be subjected to scale-up synthesis.

Nickel-Catalyzed Reductive Amidation of Aryl Fluorosulfates with Isocyanates: Synthesis of Amides via C-O Bond Cleavage.

With the assistance of nickel as catalyst, 2,2'-bipyridine (bpy) as ligand, and manganese as reducing metal, the reductive amidation of isocyanates with readily accessible aryl fluorosulfates could be successfully accomplished. The reactions proceeded effectively via C-O bond activation in DMF at room temperature, enabling the facile synthesis of a range of structurally diverse amides in moderate to high yields with broad functionality compatibility. In addition, the synthetic usefulness of the method was further demonstrated by applying the reaction in scale-up synthesis and the late-stage functionalization of complex molecules with biological activities.

Sulfonylation of Pyridyl Phosphonium Salts with Sulfinate Salts in Aqueous Media for the Synthesis of 4-Pyridyl Sulfones via C-P Bond Cleavage.

A NaSO-initiated sulfonylation of pyridyl phosphonium salts with sulfinate salts in aqueous media has been developed for facile access to 4-pyridyl sulfones. The reactions, which employed pyridyl phosphonium salts as efficient pyridylation agents via C-P bond activation, showed both broad substrate generality and good functional group compatibility. In addition, the scale-up synthesis and the late-stage modification of pharmaceutically active complex molecules (e.

Combining (CHO) and (NH)CO as a Formamidine Equivalent for "Four-in-One" Synthesis of Fluoroalkylated 2--Pyrimidines.

Multicomponent reactions hold the potential to maximize the synthetic efficiency in the preparation of diverse and complex molecular scaffolds. An unprecedented formal [3+1+1+1] annulation approach for the one-step synthesis of fluoroalkylated 2--pyrimidines commencing from perfluoroalkyl alkenes, paraformaldehyde, and ammonium carbonate is described. By harnessing readily accessible (CHO) and cheap (NH)CO as a formamidine surrogate, this method effectively replaces traditionally preformed amidines with a pyrimidine assembly.

Chemo-, regio-, and stereoselective tetrafunctionalization of fluoroalkynes enables divergent synthesis of 5-7-membered azacycles.

Alkyne annulation has been widely used in organic synthesis for the construction of azacycles with unique structural and physicochemical properties. However, the analogous transformation of fluoroalkynes remains a challenge and has seen limited progress. Herein we report a 1,2,3,4-tetrafunctionalization of polyfluoroalkynes for the divergent construction of 5-7-membered ()-1,2-difluorovinyl azacycles.

Silver-Promoted Three-Component Synthesis of Perfluoroalkenyl Pyrroles through Partial Defluorinative Functionalization of Perfluoroalkyl Halides.

A silver-promoted three-component heterocyclization of alkynes, perfluoroalkyl halides, and 1,3-dinucleophiles was developed for the efficient synthesis of privileged ()-perfluoroalkenyl pyrroles. The reaction proceeded through a rationally designed sequence of radical perfluoroalkylation and intramolecular defluorinative [3 + 2]-heterocyclization. The utility of perfluoroalkyl halide as a perfluoroalkenyl reagent, by selective and controllable functionalization of two inert C(sp)-F bonds at vicinal carbon centers on the perfluoroalkyl chain, provides a new reaction mode for the synthesis of value-added organofluorides starting from the easily available and low-cost fluorinated feedstock.